Highlights from the SNS Annual Meeting 2024 in Basel!

We are excited to share our experience from the Annual Meeting 2024 of the Swiss Neurological Society (SNS) in Basel. Our team was honored to contribute to this conference through several presentations:

• Prof. Veit Rothhammer delivered an insightful talk on “Astrocyte-produced HB-EGF limits autoimmune CNS pathology.”

• Lena Lößlein presented an engaging ePoster Flash talk.

• Anne Peter and Oliver Vandrey showcased their research with an informative poster presentation.

The meeting's theme, "Quo vadis neuroinflammation? From pathophysiologic advances to novel treatment strategies," guided a series of compelling discussions. Experts from across Switzerland and abroad explored ongoing diagnostic and therapeutic challenges, sharing the latest advancements in neuroimmunological diseases.

We are grateful for the opportunity to be part of such a distinguished event. Thank you for having us!

New Article published!

The role of midkine in health and disease

Emely Elisa Neumaier, Veit Rothhammer*, Mathias Linnerbauer

Abstract
Midkine (MDK) is a neurotrophic growth factor highly expressed during embryogenesis with important functions related to growth, proliferation, survival, migration, angiogenesis, reproduction, and repair. Recent research has indicated that MDK functions as a key player in autoimmune disorders of the central nervous system (CNS), such as Multiple Sclerosis (MS) and is a promising therapeutic target for the treatment of brain tumors, acute injuries, and other CNS disorders. This review summarizes the modes of action and immunological functions of MDK both in the peripheral immune compartment and in the CNS, particularly in the context of traumatic brain injury, brain tumors, neuroinflammation, and neurodegeneration. Moreover, we discuss the role of MDK as a central mediator of neuro-immune crosstalk, focusing on the interactions between CNS-infiltrating and -resident cells such as astrocytes, microglia, and oligodendrocytes. Finally, we highlight the therapeutic potential of MDK and discuss potential therapeutic approaches for the treatment of neurological disorders.

Frontiers in Immunology. 2023. https://doi.org/10.3389/fimmu.2023.1310094

New Article published!

Intranasal delivery of a small-molecule ErbB inhibitor promotes recovery from acute and late-stage CNS inflammation

Mathias Linnerbauer, Lena Lößlein, Oliver Vandrey, Thanos Tsaktanis, Alexander Beer, Ulrike J. Naumann, Franziska Panier, Tobias Beyer, Lucy Nirschl, Joji B. Kuramatsu, Jürgen Winkler, Francisco J. Quintana, and Veit Rothhammer

Abstract
Multiple sclerosis (MS) is an autoimmune inflammatory disease of the CNS that is characterized by demyelination and axonal degeneration. Although several established treatments reduce relapse burden, effective treatments to halt chronic progression are scarce. Single-cell transcriptomic studies in MS and its animal models have described astrocytes and their spatial and functional heterogeneity as important cellular determinants of chronic disease. We combined CNS single-cell transcriptome data and small-molecule screens in primary mouse and human astrocytes to identify glial interactions, which could be targeted by repurposing FDA-approved small-molecule modulators for the treatment of acute and late-stage CNS inflammation. Using hierarchical in vitro and in vivo validation studies, we demonstrate that among selected pathways, blockade of ErbB by the tyrosine kinase inhibitor afatinib efficiently mitigates proinflammatory astrocyte polarization and promotes tissue-regenerative functions. We found that i.n. delivery of afatinib during acute and late-stage CNS inflammation ameliorates disease severity by reducing monocyte infiltration and axonal degeneration while increasing oligodendrocyte proliferation. We used unbiased screening approaches of astrocyte interactions to identify ErbB signaling and its modulation by afatinib as a potential therapeutic strategy for acute and chronic stages of autoimmune CNS inflammation.

JCI Insight 2022. 10.1172/jci.insight.154824

New Article published!

Astrocyte-Derived Pleiotrophin Mitigates Late-Stage Autoimmune CNS Inflammation

Mathias Linnerbauer, Lena Lößlein, Oliver Vandrey, Thanos Tsaktanis, Alexander Beer, Ulrike J. Naumann, Franziska Panier, Tobias Beyer, Lucy Nirschl, Joji B. Kuramatsu, Jürgen Winkler, Francisco J. Quintana, and Veit Rothhammer

Abstract
Multiple sclerosis (MS) is an autoimmune inflammatory disease of the CNS that is characterized by demyelination and axonal degeneration. Although several established treatments reduce relapse burden, effective treatments to halt chronic progression are scarce. Single-cell transcriptomic studies in MS and its animal models have described astrocytes and their spatial and functional heterogeneity as important cellular determinants of chronic disease. We combined CNS single-cell transcriptome data and small-molecule screens in primary mouse and human astrocytes to identify glial interactions, which could be targeted by repurposing FDA-approved small-molecule modulators for the treatment of acute and late-stage CNS inflammation. Using hierarchical in vitro and in vivo validation studies, we demonstrate that among selected pathways, blockade of ErbB by the tyrosine kinase inhibitor afatinib efficiently mitigates proinflammatory astrocyte polarization and promotes tissue-regenerative functions. We found that i.n. delivery of afatinib during acute and late-stage CNS inflammation ameliorates disease severity by reducing monocyte infiltration and axonal degeneration while increasing oligodendrocyte proliferation. We used unbiased screening approaches of astrocyte interactions to identify ErbB signaling and its modulation by afatinib as a potential therapeutic strategy for acute and chronic stages of autoimmune CNS inflammation.

JCI Insight 2022. 10.1172/jci.insight.154824

Looking for student assistant (HiWi)

The Rothhammer Lab is looking for a HiWi (student assistant) to assist in daily lab work and help to investigate novel mechanisms in glial cell biology during autoimmune inflammatory and degenerative diseases of the central nervous system.

Project:

The student will work together with PhD’s on their respective projects - perform and analyse experiments, assist in daily lab work and participate in regular meetings.

Canidates:

Candidates should hold or pursue a degree biomedical research, bioengineering or related areas and exhibit strong interest and experience in tackling advanced biomedical questions related to autoimmune and degenerative diseases of the central nervous system.

Experience with the following techniques is advantageous, but not necessary:

• Experience in mouse handling

• In vitro assays involving primary glial cells

• Standard PCR, RT-qPCR

• microscopy

Offer:

We offer a young and dynamic research environment in a fully equipped and experienced wet and translational laboratory, which will allow candidates to establish and expand their skill set with high relevance for basic and translational research.⠀

Funding will be supplied in form of a minijob.

Please apply by submitting an e-mail to veit.rothhammer@fau.de or using the contact form on the website.

New Article published!

The Aryl Hydrocarbon Receptor–Dependent TGF-α/VEGF-B Ratio Correlates With Disease Subtype and Prognosis in Multiple Sclerosis

Ana Cirac, Thanos Tsaktanis, Tobias Beyer, Mathias Linnerbauer, Till Andlauer, Verena Grummel, Lucy Nirschl, Lena Loesslein, Francisco J. Quintana, Bernhard Hemmer, Veit Rothhammer

Abstract
Objective To evaluate the aryl hydrocarbon receptor (AHR)-dependent transforming growth factor alpha (TGF-α)/vascular endothelial growth factor B (VEGF-B) ratio, which regulates the effects of metabolic, dietary, and microbial factors on acute and chronic CNS inflammation, as a potential marker in multiple sclerosis (MS).

Methods TGF-α, VEGF-B, and AHR agonistic activity were determined in serum of 252 patients with relapsing-remitting (RR) MS, primary and secondary progressive MS, as well as during active disease (clinically isolated syndrome [CIS] and RRMS relapse).

Results The TGF-α/VEGF-B ratio and AHR agonistic activity were decreased in all MS subgroups with a stable disease course as compared to controls. During active CNS inflammation in CIS and RRMS relapse, the TGF-α/VEGF-B ratio and AHR agonistic activity were increased. Conversely, in patients with minimal clinical impairment despite long-standing disease, the TGF-α/VEGF-B ratio and AHR agonistic activity were unaltered. Finally, the TGF-α/VEGF-B ratio and AHR agonistic activity correlated with neurologic impairment and time to conversion from CIS to MS.

Conclusions The AHR-dependent TGF-α/VEGF-B ratio is altered in a subtype, severity, and disease activity–specific manner and correlates with time to conversion from CIS to MS. It may thus represent a novel marker and serve as additive guideline for immunomodulatory strategies in MS.

Neurology Neuroimmunology & Neuroinflammation, 2021. DOI: https://doi.org/10.1212/NXI.0000000000001043

Currently open: PostDoc (M/F/D) Position

The Rothhammer Lab is looking for an experienced PostDoc to investigate novel mechanisms in glial cell biology during autoimmune inflammatory and degenerative diseases of the central nervous system.

Project:

The PostDoc will work on fascinating projects focusing on glial signaling in acute and chronic stages of autoimmune inflammation in the central nervous system, as well as its modulation by environmental and microbial factors

Canidates:

Candidates should hold a PhD degree in biomedical research, bioengineering or related areas and exhibit strong interest and experience in tackling advanced biomedical questions related to autoimmune and degenerative diseases of the central nervous system. The successful PostDoc candidate should furthermore have experience with the guidance and supervision of PhD and medical students in a multidisciplinary environment.

Experience with the following techniques is advantageous, but not necessary:

• Multi-parameter Flow cytometry

• Rodent models of experimental autoimmune encephalomyelitis

• In vitro assays involving primary glial cells

• Genome editing techniques (e.g. CRISPR/Cas9)

• High throughput transcriptomic and proteomic profiling

Offer:

We offer a young and dynamic research environment in a fully equipped and experienced wet and translational laboratory, which will allow candidates to establish and expand their skill set with high relevance for basic and translational research.⠀

The University Hospital together with the Friedrich-Alexander-Universität (FAU) Erlangen are committed to become the “City of Health and Medicine”. Within the scope of “Medical Valley EMN” (a scientific cluster-cooperation) the University Hospital, FAU and the City Erlangen are collaborating with scientific, commercial and political partners to gain an international leadership position in the field of health care and medical research. ⠀⠀ ⠀⠀⠀⠀ ⠀⠀⠀⠀ ⠀

Funding will be supplied according to TV-L.

Apply:⠀⠀⠀ ⠀⠀⠀⠀ ⠀⠀⠀⠀ ⠀⠀⠀⠀ ⠀⠀⠀⠀ ⠀⠀⠀⠀ ⠀⠀⠀⠀ ⠀⠀⠀⠀ ⠀⠀⠀⠀ ⠀⠀⠀⠀ ⠀⠀⠀⠀ ⠀⠀⠀⠀ ⠀

The position is open immediately. Please submit your application (including a CV and a letter of interest) via E-Mail to Prof. Veit Rothhammer or using the contact formular provided on the Webpage. This is a rolling application, which will remain active until the position is filled.

2 new Articles published!

Happy New Year from the Rothhammer Lab!

We had a great start into the new year and are pleased to share our two most recent publications!

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A cell-based drug delivery platform for treating central nervous system inflammation

Oren Levy*, Veit Rothhammer*, Ivan Mascanfroni, Zhixiang Tong, Rui Kuai, Michael De Biasio, Qingping Wang, Tahir Majid, Christelle Perrault, Ada Yeste, Jessica E. Kenison, Helia Safaee, Juliet Musabeyezu, Martina Heinelt, Yuka Milton, Heidi Kuang, Haoyue Lan, William Siders, Marie-Christine Multon, Jonathan Rothblatt, Salam Massadeh, Manal Alaamery, Ali H. Alhasan, Francisco J. Quintana & Jeffrey M. Karp

J Mol Med (2021). https://doi.org/10.1007/s00109-020-02003-9

Abstract
Mesenchymal stem cells (MSCs) are promising candidates for the development of cell-based drug delivery systems for autoimmune inflammatory diseases, such as multiple sclerosis (MS). Here, we investigated the effect of Ro-31-8425, an ATP-competitive kinase inhibitor, on the therapeutic properties of MSCs. Upon a simple pretreatment procedure, MSCs spontaneously took up and then gradually released significant amounts of Ro-31-8425. Ro-31-8425 (free or released by MSCs) suppressed the proliferation of CD4+ T cells in vitro following polyclonal and antigen-specific stimulation. Systemic administration of Ro-31-8425-loaded MSCs ameliorated the clinical course of experimental autoimmune encephalomyelitis (EAE), a murine model of MS, displaying a stronger suppressive effect on EAE than control MSCs or free Ro-31-8425. Ro-31-8425-MSC administration resulted in sustained levels of Ro-31-8425 in the serum of EAE mice, modulating immune cell trafficking and the autoimmune response during EAE. Collectively, these results identify MSC-based drug delivery as a potential therapeutic strategy for the treatment of autoimmune diseases.

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Aryl Hydrocarbon Receptor Activation in Astrocytes by Laquinimod Ameliorates Autoimmune Inflammation in the CNS

Rothhammer V, Kenison JE, Li Z, Tjon E, Takenaka MC, Chao CC, Alves de Lima K, Borucki DM, Kaye J, Quintana FJ.

Neurol Neuroimmunol Neuroinflamm. 2021. doi: 10.1212/NXI.0000000000000946.

Abstract
Objective: MS is an autoimmune demyelinating disease of the CNS, which causes neurologic deficits in young adults and leads to progressive disability. The aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, can drive anti-inflammatory functions in peripheral immune cells and also in CNS-resident cells. Laquinimod is a drug developed for the treatment of MS known to activate AHR, but the cellular targets of laquinimod are still not completely known. In this work, we analyzed the contribution of AHR activation in astrocytes to its beneficial effects in the experimental autoimmune encephalomyelitis (EAE) preclinical model of MS.

Methods: We used conditional knockout mice, in combination with genome-wide analysis of gene expression by RNA-seq and in vitro culture systems to investigate the effects of laquinimod on astrocytes.

Results: We found that AHR activation in astrocytes by laquinimod ameliorates EAE, a preclinical model of MS. Genome-wide RNA-seq transcriptional analyses detected anti-inflammatory effects of laquinimod in glial cells during EAE. Moreover, we established that the Delaq metabolite of laquinimod dampens proinflammatory mediator production while activating tissue-protective mechanisms in glia.

Conclusions: Taken together, these findings suggest that AHR activation by clinically relevant AHR agonists may represent a novel therapeutic approach for the treatment of MS.

New Article published!

Aryl Hydrocarbon Receptor Plasma Agonist Activity Correlates With Disease Activity in Progressive MS

Thanos Tsaktanis, Tobias Beyer, Lucy Nirschl, Mathias Linnerbauer, Verena Grummel, Mathias Bussas, Emily Tjon, Mark Mühlau, Thomas Korn, Bernhard Hemmer, Francisco J. Quintana, Veit Rothhammer

Abstract
Objective The relationship between serum aryl hydrocarbon receptor (AHR) agonistic activity levels with disease severity, its modulation over the course of relapsing-remitting MS (RRMS), and its regulation in progressive MS (PMS) are unknown. Here, we report the analysis of AHR agonistic activity levels in cross-sectional and longitudinal serum samples of patients with RRMS and PMS.

Methods In a cross-sectional investigation, a total of 36 control patients diagnosed with noninflammatory diseases, 84 patients with RRMS, 35 patients with secondary progressive MS (SPMS), and 41 patients with primary progressive MS (PPMS) were included in this study. AHR activity was measured in a cell-based luciferase assay and correlated with age, sex, the presence of disease-modifying therapies, Expanded Disability Status Scale scores, and disease duration. In a second longitudinal investigation, we analyzed AHR activity in 13 patients diagnosed with RRMS over a period from 4 to 10 years and correlated AHR agonistic activity with white matter atrophy and lesion load volume changes.

Results In RRMS, AHR ligand levels were globally decreased and associated with disease duration and neurologic disability. In SPMS and PPMS, serum AHR agonistic activity was decreased and correlated with disease severity. Finally, in longitudinal serum samples of patients with RRMS, decreased AHR agonistic activity was linked to progressive CNS atrophy and increased lesion load.

Conclusions These findings suggest that serum AHR agonist levels negatively correlate with disability in RRMS and PMS and decrease longitudinally in correlation with MRI markers of disease progression. Thus, serum AHR agonistic activity may serve as novel biomarker for disability progression in MS.

Neurology Neuroimmunology & Neuroinflammation, 2020. https://doi.org/10.1212/NXI.0000000000000933

Prof. Veit Rothhammer receives MS Award

Prof. Veit Rothhammer receives MS Award from the Bavarian Academy of Sciences and Humanities

Prof. Veit Rothhammer was awarded the Karl-Heinz Hoffmann Award for his outstanding contributions to MS research and other neuroimmunological conditions. The award, which is supported by the entrepreneur Ulrich L. Rohde, is given to excellent junior researcher in the field of natural sciences and humanities.

We say congrats Prof. Rothhammer!

Open PhD (m/f/d) Position

The Rothhammer Lab is looking for an ambitious PhD to investigate novel mechanisms in glial cell biology during autoimmune inflammatory and degenerative diseases of the central nervous system.

Project:

The PhD will work on fascinating projects focusing on glial signaling in acute and chronic stages of autoimmune inflammation in the central nervous system, as well as its modulation by environmental and microbial factors

Canidates:

Candidates should hold a Master’s degree (or equivalent) in biomedical research, bioengineering or related areas and possess a strong interest to unravel immunological questions in inflammatory and degenerative diseases with the goal of developing novel therapeutic strategies. 

Experience with the following techniques is advantageous, but not necessary:

• Multi-parameter Flow cytometry

• Rodent models of experimental autoimmune encephalomyelitis

• In vitro assays involving primary glial cells⠀⠀⠀ ⠀⠀⠀⠀ ⠀⠀⠀⠀ ⠀⠀⠀⠀ ⠀⠀⠀⠀ ⠀⠀⠀⠀ ⠀⠀⠀⠀ ⠀⠀⠀⠀ ⠀⠀⠀⠀ ⠀⠀⠀⠀ ⠀⠀⠀⠀ ⠀⠀⠀⠀ ⠀

Offer:

We offer a young and dynamic research environment in a fully equipped and experienced wet and translational laboratory, which will allow candidates to establish and expand their skill set with high relevance for basic and translational research.⠀

The University Hospital together with the Friedrich-Alexander-Universität (FAU) Erlangen are committed to become the “City of Health and Medicine”. Within the scope of “Medical Valley EMN” (a scientific cluster-cooperation) the University Hospital, FAU and the City Erlangen are collaborating with scientific, commercial and political partners to gain an international leadership position in the field of health care and medical research. ⠀⠀ ⠀⠀⠀⠀ ⠀⠀⠀⠀ ⠀

Funding will be supplied according to TV-L.

Apply:⠀⠀⠀ ⠀⠀⠀⠀ ⠀⠀⠀⠀ ⠀⠀⠀⠀ ⠀⠀⠀⠀ ⠀⠀⠀⠀ ⠀⠀⠀⠀ ⠀⠀⠀⠀ ⠀⠀⠀⠀ ⠀⠀⠀⠀ ⠀⠀⠀⠀ ⠀⠀⠀⠀ ⠀

The position is open immediately. Please submit your application (including a CV and a letter of interest) via E-Mail to Prof. Veit Rothhammer or using the contact formular provided on the Webpage. This is a rolling application, which will remain active until the position is filled.

New Review published!

Protective Functions of Reactive Astrocytes Following Central Nervous System Insult

Mathias Linnerbauer, Veit Rothhammer

Abstract
Astrocytes play important roles in numerous central nervous system disorders including autoimmune inflammatory, hypoxic and degenerative diseases such as Multiple Sclerosis, ischemic stroke and Alzheimer’s disease. Depending on the spatial and temporal context, activated astrocytes may contribute to the pathogenesis, progression, and recovery of disease. Recent progress in the dissection of transcriptional responses to varying forms of central nervous system insult has shed light on the mechanisms that govern the complexity of reactive astrocyte functions. While a large body of research focuses on the pathogenic effects of reactive astrocytes, little is known about how they limit inflammation and contribute to tissue regeneration. However, these protective astrocyte pathways might be of relevance for the understanding of the underlying pathology in disease and may lead to novel targeted approaches to treat autoimmune inflammatory and degenerative disorders of the central nervous system. In this review article, we have revisited the emerging concept of protective astrocyte functions and discuss their role in the recovery from inflammatory and ischemic disease as well as their role in degenerative disorders. Focusing on soluble astrocyte derived mediators, we aggregate the existing knowledge on astrocyte functions in the maintenance of homeostasis as well as their reparative and tissue-protective function after acute lesions and in neurodegenerative disorders. Finally, we give an outlook of how these mediators may guide future therapeutic strategies to tackle hence untreatable disorders of the central nervous system.

Front. Immunol. 2020. doi: 10.3389/fimmu.2020.573256